CERVO Brain Research Centre, 2601 de la Canardière, Québec, QC G1J 2G3, Canada.
CERVO Brain Research Centre, 2601 de la Canardière, Québec, QC G1J 2G3, Canada; Department of Biochemistry, Microbiology and Bioinformatics, Faculty of Science and Engineering, Université Laval, Québec, QC G1V 0A6, Canada.
Cell Rep. 2020 Feb 18;30(7):2374-2386.e5. doi: 10.1016/j.celrep.2020.01.084.
The neurodevelopmental origin of hyperactivity disorder has been suggested to involve the dopaminergic system, but the underlying mechanisms are still unknown. Here, transcription factors Lmx1a and Lmx1b are shown to be essential for midbrain dopaminergic (mDA) neuron excitatory synaptic inputs and dendritic development. Strikingly, conditional knockout (cKO) of Lmx1a/b in postmitotic mDA neurons results in marked hyperactivity. In seeking Lmx1a/b target genes, we identify positively regulated Slitrk2 and negatively regulated Slitrk5. These two synaptic adhesion proteins promote excitatory and inhibitory synapses on mDA neurons, respectively. Knocking down Slitrk2 reproduces some of the Lmx1a/b cKO cellular and behavioral phenotypes, whereas Slitrk5 knockdown has opposite effects. The hyperactivity caused by this imbalance in excitatory/inhibitory synaptic inputs on dopamine neurons is reproduced by chronically inhibiting the ventral tegmental area during development using pharmacogenetics. Our study shows that alterations in developing dopaminergic circuits strongly impact locomotor activity, shedding light on mechanisms causing hyperactivity behaviors.
注意到转录因子 Lmx1a 和 Lmx1b 对于中脑多巴胺能（mDA）神经元兴奋性突触输入和树突发育至关重要。令人惊讶的是，条件性敲除（cKO）处于有丝分裂后的 mDA 神经元中的 Lmx1a/b 导致明显的多动。在寻找 Lmx1a/b 的靶基因时，我们确定了 Slitrk2 的正调控和 Slitrk5 的负调控。这两种突触粘附蛋白分别促进 mDA 神经元上的兴奋性和抑制性突触。Slitrk2 的敲低再现了 Lmx1a/b cKO 的一些细胞和行为表型，而 Slitrk5 的敲低则有相反的效果。通过使用药物遗传学在发育过程中慢性抑制腹侧被盖区，复制了多巴胺神经元上兴奋性/抑制性突触输入失衡引起的多动。我们的研究表明，发育中的多巴胺能回路的改变强烈影响运动活动，为引起多动行为的机制提供了线索。
